Influencing the tumor microenvironment: A Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases

Research output: Contribution to journalArticle

Nancy Chan, Amy Willis, Naomi Kornhauser, Maureen Mward, Sharrell B. Lee, Eleni Nackos, Bo Ri Seo, Ellen Chuang, Tessa Cigler, Anne Moore, Diana Donovan, Marta Vallee Cobham, Veronica Fitzpatrick, Sarah Schneider, Alysia Wiener, Jessica Guillaume-Abraham, Elnaz Aljom, Richard Zelkowitz, J. David Warren, Maureen E. Lane & 3 others Claudia Fischbach, Vivek Mittal, Linda Vahdat

Purpose: Bone marrow-derived progenitor cells, including VEGFR2 endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P <0.001). Two-year EFS for patients with stage II-III and stage IVNED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.

Original languageEnglish (US)
Pages (from-to)666-676
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number3
DOIs
StatePublished - Feb 1 2017

PMID: 27769988

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Influencing the tumor microenvironment : A Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. / Chan, Nancy; Willis, Amy; Kornhauser, Naomi; Mward, Maureen; Lee, Sharrell B.; Nackos, Eleni; Seo, Bo Ri; Chuang, Ellen; Cigler, Tessa; Moore, Anne; Donovan, Diana; Cobham, Marta Vallee; Fitzpatrick, Veronica; Schneider, Sarah; Wiener, Alysia; Guillaume-Abraham, Jessica; Aljom, Elnaz; Zelkowitz, Richard; Warren, J. David; Lane, Maureen E.; Fischbach, Claudia; Mittal, Vivek; Vahdat, Linda.

In: Clinical Cancer Research, Vol. 23, No. 3, 01.02.2017, p. 666-676.

Research output: Contribution to journalArticle

Harvard

Chan, N, Willis, A, Kornhauser, N, Mward, M, Lee, SB, Nackos, E, Seo, BR, Chuang, E, Cigler, T, Moore, A, Donovan, D, Cobham, MV, Fitzpatrick, V, Schneider, S, Wiener, A, Guillaume-Abraham, J, Aljom, E, Zelkowitz, R, Warren, JD, Lane, ME, Fischbach, C, Mittal, V & Vahdat, L 2017, 'Influencing the tumor microenvironment: A Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases' Clinical Cancer Research, vol. 23, no. 3, pp. 666-676. https://doi.org/10.1158/1078-0432.CCR-16-1326

APA

Chan, N., Willis, A., Kornhauser, N., Mward, M., Lee, S. B., Nackos, E., ... Vahdat, L. (2017). Influencing the tumor microenvironment: A Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clinical Cancer Research, 23(3), 666-676. https://doi.org/10.1158/1078-0432.CCR-16-1326

Vancouver

Chan N, Willis A, Kornhauser N, Mward M, Lee SB, Nackos E et al. Influencing the tumor microenvironment: A Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clinical Cancer Research. 2017 Feb 1;23(3):666-676. https://doi.org/10.1158/1078-0432.CCR-16-1326

Author

Chan, Nancy ; Willis, Amy ; Kornhauser, Naomi ; Mward, Maureen ; Lee, Sharrell B. ; Nackos, Eleni ; Seo, Bo Ri ; Chuang, Ellen ; Cigler, Tessa ; Moore, Anne ; Donovan, Diana ; Cobham, Marta Vallee ; Fitzpatrick, Veronica ; Schneider, Sarah ; Wiener, Alysia ; Guillaume-Abraham, Jessica ; Aljom, Elnaz ; Zelkowitz, Richard ; Warren, J. David ; Lane, Maureen E. ; Fischbach, Claudia ; Mittal, Vivek ; Vahdat, Linda. / Influencing the tumor microenvironment : A Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 3. pp. 666-676.

BibTeX

@article{601d9ebb235441558f6a8e11f4a792ac,
title = "Influencing the tumor microenvironment: A Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases",
abstract = "Purpose: Bone marrow-derived progenitor cells, including VEGFR2 endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7{\%}). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P <0.001). Two-year EFS for patients with stage II-III and stage IVNED was 91{\%} and 67{\%}, respectively. For patients with TNBC, EFS was 90{\%} (adjuvant patients) and 50{\%} (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.",
keywords = "Department of medicine, New York, Weill cornell medicine",
author = "Nancy Chan and Amy Willis and Naomi Kornhauser and Maureen Mward and Lee, {Sharrell B.} and Eleni Nackos and Seo, {Bo Ri} and Ellen Chuang and Tessa Cigler and Anne Moore and Diana Donovan and Cobham, {Marta Vallee} and Veronica Fitzpatrick and Sarah Schneider and Alysia Wiener and Jessica Guillaume-Abraham and Elnaz Aljom and Richard Zelkowitz and Warren, {J. David} and Lane, {Maureen E.} and Claudia Fischbach and Vivek Mittal and Linda Vahdat",
year = "2017",
month = "2",
day = "1",
doi = "10.1158/1078-0432.CCR-16-1326",
language = "English (US)",
volume = "23",
pages = "666--676",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

RIS

TY - JOUR

T1 - Influencing the tumor microenvironment

T2 - Clinical Cancer Research

AU - Chan, Nancy

AU - Willis, Amy

AU - Kornhauser, Naomi

AU - Mward, Maureen

AU - Lee, Sharrell B.

AU - Nackos, Eleni

AU - Seo, Bo Ri

AU - Chuang, Ellen

AU - Cigler, Tessa

AU - Moore, Anne

AU - Donovan, Diana

AU - Cobham, Marta Vallee

AU - Fitzpatrick, Veronica

AU - Schneider, Sarah

AU - Wiener, Alysia

AU - Guillaume-Abraham, Jessica

AU - Aljom, Elnaz

AU - Zelkowitz, Richard

AU - Warren, J. David

AU - Lane, Maureen E.

AU - Fischbach, Claudia

AU - Mittal, Vivek

AU - Vahdat, Linda

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Purpose: Bone marrow-derived progenitor cells, including VEGFR2 endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P <0.001). Two-year EFS for patients with stage II-III and stage IVNED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.

AB - Purpose: Bone marrow-derived progenitor cells, including VEGFR2 endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P <0.001). Two-year EFS for patients with stage II-III and stage IVNED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.

KW - Department of medicine

KW - New York

KW - Weill cornell medicine

UR - http://www.scopus.com/inward/record.url?scp=85012865407&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85012865407&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-16-1326

DO - 10.1158/1078-0432.CCR-16-1326

M3 - Article

VL - 23

SP - 666

EP - 676

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 3

ER -

ID: 29158330